Moving up the river from the Mandan villages, they passed the confluence of the Yellowstone with the Missouri, and entered a country where Lewis observed "immence herds of Buffaloe, Elk, deer & Antelopes feeding in one common and boundless pasture." Grizzly bears charged the men hunting them.

Lewis commented that he would "reather fight two Indians than one bear." River navigation became more difficult. During a fierce windstorm, the pirogue that carried important records and instruments began filling with water and nearly capsized. Sacagawea, who was aboard, saved many items as they floated within her reach. Near the end of May, the Rocky Mountains came into view.
The river's current grew stronger. The explorers had to abandon the paddles and tow the heavy canoes with rawhide ropes while walking along the shoreline. When river banks gave way to cliffs the men had to wade in the water, pushing and pulling the boats upstream.

In early June, the explorers reached a point where the Missouri seemed to divide equally into northerly and southerly branches. Here they spent nine days in concluding that the south branch was the true Missouri. Lewis named the north fork the Marias River, and scouted ahead with a small advance party following the south fork until he heard waterfalls. The Indians at Fort Mandan had told them about the falls of the Missouri, so Lewis knew he was on the right stream.

Here, in the vicinity of present-day Great Falls, Montana, the Expedition had to portage 18 miles around a series of five cascades of the Missouri. The men attached cottonwood wheels to the canoes to push them overland. The weather was hot, with intermittent squalls pelting the party with large, bruising hailstones.

Transporting the heavy boats and baggage up the steep incline from the river and traversing the long stretch of prairie lands was an exhausting ordeal. Prickly pear spines penetrated their feet through moccasin soles, adding to the difficult and exhausting portage.

After shuttling canoes and baggage along this portage for three weeks, a camp was established above the falls at "White bear Island." They had brought along a metal framework over which they stretched hides to make a large, light boat to resume their journey on the river. The plan failed when stitches in the hides leaked water. They had to abandon the framework and make two more cottonwood canoes.